Acute Kidney Injury to Chronic Kidney Disease Transition ESRD AKI CKD

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1 Acute Kidney Injury to Chronic Kidney Disease Transition AKI Hypoxia Capillary Rarefaction Partial EMT Pericytes ESRD CKD Mark D. Okusa, M.D. Chief, Division of Nephrology Center for Immunity, Inflammation and Regenerative Medicine University of Virginia Health System Mitochondria Metabolic Switch

8% women 7,000,000 ESRD 3,900,000 Treated with RRT P. Susantitaphong et al. Am J.

2 850,000,000+ People world wide have kidney diseases 40 M 13,300,000 Acute Kidney Injury 843,000,000 CKD % men and 11.8% women 7,000,000 ESRD 3,900,000 Treated with RRT P. Susantitaphong et al. Am J. Kid Dis (2013)61, K.T. Mills et al., Kidney International (2015) 88, T. Liyanage et al. Lancet (2015) 385,

3 AKI, CKD and ESRD 84 YOM with stage IV CKD, DM-2, CHF, COPD admitted with hypoglycemia, SBO with nausea and vomiting. Pt was volume depleted with SCr of 5.5. From Bruce Molitoris

4 Systematic review of chronic kidney disease and ESRD associated with acute kidney injury CKD ESRD S. Coca, Singanamala, C. Parikh. Kidney Int advance online publication 23 November 2011; doi: /ki

Mortality after acute kidney injury Traditional risk factors, such as chronic hypertension, dyslipidemia contribute LVH in CKD affects 50% 70% of

5 Mortality after acute kidney injury Traditional risk factors, such as chronic hypertension, dyslipidemia contribute LVH in CKD affects 50% 70% of patients during intermediate stages of CKD 90% of patients by the time they reach dialysis S. Coca, et al. Kidney International (2012) 81,

6 CKD increases sensitivity to CV events Loss of Windkessel Physiology Arterial Calcification Scialla, J. J. & Wolf, M. (2014) Nat. Rev. Nephrol B. Thompson and D. A. Towler Nat. Rev. Endocrinol. 8, (2012)

7 C. Faul et al. J Clin Invest. 2011;121(11):

sulfotransferase-mediated sulfate conjugation.

8 Indoxyl sulfate and PAD Indoxyl sulfate (IS) is produced by intestinal bacteria; degradation product of tryptophan; in liver IS is produced by cytochrome P450 mediated hydroxylation of indole to indoxyl, f/b sulfotransferase-mediated sulfate conjugation. AST-120 an adsorbent reverses effect of IS, in clinic trials (ClinicalTrials.gov). L Dou and S. Burtey Kidney Int 89:532, 534, 2016 S-C Hung S-C, et al. Kidney Int. 2016;89:

9 Normal Repair AKI-CKD Redifferentiation, recovery vs failed redifferentiation and growth arrest x Canaud, Bonventre. Nephrol Dial Transplant. 2015; 30(4): M.A. Venkatachalam et al. JASN 26: , 2015

insult, continued inflammation, hypoxia or hyperfiltration in remnant

10 Failed tubule differentiation and atrophy and Fibrosis is restricted to diseased microenvironment Extension of fibrosis requires additional insult, continued inflammation, hypoxia or hyperfiltration in remnant nephrons M.A. Venktatachalam et al. Am Soc Nephrol 26: , 2015d

11 Collagen, matrix and interstitial proliferation vehicle 7d folic acid 7d CORTEX MEDULLA 20x A. Bajwa, et al. J. Am. Soc. Nephrol. Apr 1, : A. Bajwa, et al. J. Am. Soc. Nephrol. Apr 1, :

12 Nexus of AKI and CKD/ESRD Cardiovascular Events AKI Age Outcomes Racial/ethnic group Disease Modifiers Severity of AKI CKD Stage No Episodes Genetic factors Duration of AKI Hypertension Diabetes Proteinuria Metabolic syndrome Disability and Diminished QOL CKD ESRD Risk Factors Death

13 Capillary Dropout In Postischemic Kidney 20 µm Microfil-infused Kidney Sections Sha m 4 weeks 8 weeks DP Basile et al. AJP Renal 281: F887-F899, 2001

14 High-Resolution in vivo ex vivo Micro CT Ex vivo Microfil Perfusion and Vascular Casting In vivo Contrast Enhanced J. Ehlig et al. J Am Soc Nephrol 27: , 2016

15 Renal Vasculature following acute kidney injury J. Ehlig et al. J Am Soc Nephrol 27: , 2016

16 Capillary rarefaction increases the diffusion distance for oxygen transport in tissues Region of Hypoxia Region of Hypoxia Trzeciak S et al. Acad Emerg Med 2008; 15:

17 Loss of Peritubular Capillaries Leads to Chronic Hypoxia. M Nangaku, JASN 2006;17:17-25

Tubule specific injury can drive fibrosis: Tansgenic mice overexpressing KIM-1 in proximal tubules leads to progressive fibrosis Tubules and capillaries are simultaneously injured Direct tubule

18 Tubule specific injury can drive fibrosis: Tansgenic mice overexpressing KIM-1 in proximal tubules leads to progressive fibrosis Tubules and capillaries are simultaneously injured Direct tubule damage can be sufficient to induce fibrosis Folic acid induces loss of VEGFA - fibrosis and capillary loss and interstitial fibrosis. HT Yuan et al. Am J Pathol 163: , 2003 Maleic Acid: capillary rarefaction and interstitial fibrosis R. Lan et al. Am J Physiol Renal Physiol 302: F1210 F1223, 2012 Diptheria toxin: BD Humphreys. J Clin Invest 123: , 2013 B.D. Humphreys, J.V Bonventre et al. J Clin Invest 123: , 2013

Adhesion WT Capillary Obstruction and Continued Ischemia EC S1P1 KO Extension of ARF TA Sutton, CJ Fisher, BA Molitoris Kidney Int (2002)

19 EC KO Inflammation WT Endothelium Microvascular endothelial injury and dysfunction during IRI: Endothelial Sphingosine 1 phosphate receptor 1 Ischemia Endothelial Cell activation, Dysfunction, Injury and/or Detachment Impaired Vasodilation Coagulation Leukocyte Adhesion WT Capillary Obstruction and Continued Ischemia EC S1P1 KO Extension of ARF TA Sutton, CJ Fisher, BA Molitoris Kidney Int (2002) 62, Rabelink, T. J. et al. Nat. Rev. Nephrol. 6, (2010); H. Perry and MD Okusa et al. J Am Soc Nephrol Nov;27(11):

Class II Red = F4/80 Sharfuddin, A. A. & Molitoris, B. A. (2011) Nat.

20 Acute Kidney Injury Pathogenesis Endothelial, Epithelial, Immune Cells and Interstitium Green = CX3CR1-GFP Red = MHC Class II Red = F4/80 Sharfuddin, A. A. & Molitoris, B. A. (2011) Nat. Rev. Nephrol. L. Li et al. Kidney Int :

21 Chronic Inflammation and Fibrosis: Microenvironment Diabetes Foreign Body Autoimmunity Infectious agents Tumor Inflammation Adapted from G. Wick et al. Annu. Rev. Immunol :107 35

22 Origin of myofibroblasts in the kidney 10% 60% s 5% 30% VS LeBleau R. Kalluri et al. Nature Medicine 19, (2013)

Pericytes: interstitial fibrosis after AKI Pericytes are contractile cells that wrap around endothelial cells and line capillaries and contact tubules.

23 Pericytes: interstitial fibrosis after AKI Pericytes are contractile cells that wrap around endothelial cells and line capillaries and contact tubules. Communicate with endothelial cells by contact and paracrine signaling. After injury PC-EC detachment occurs from EC: PDGFRb-mediated migration and transformation of fibroblasts/pericytes myofibroblasts causing loss of endothelial integrity. The microenvironment activates interstitial precursor cells that become myofibroblasts proliferate and make connective tissue humoral factors from regenerating tubules Inflammatory cells, including monocytes, lymphocytes, and dendritic cells By lineage analysis are derived from FoxD1 expressing embryonic progenitors. B. D. Humphreys. Semin Nephrol Sep; 32(5):

24 Endothelial Cells and Pericytes in Fibrosis J. Duffield J Clin Invest. 2014;124(6):

25 Expansion of Labeled Interstitial Pericytes During Fibrosis BD Humphreys, JS Duffield et al. Am J Pathol 176:85-97, 2010

26 Pericytes detach from endothelial cells following IRI R. Kramann, et al. J Am Soc Nephrol 28: , 2017

27 Capillary rarefaction after Gli1+ pericyte ablation Importance of PC-EC contact to maintain normal function R. Kramann, et al. J Am Soc Nephrol 28: , 2017

28 Phase-dependent macrophage phenotypic change during the progress of kidney diseases Q. Cao et al. PHYSIOLOGY 30: , 2015 L. Li et al. Kidney Int : M1

29 Microenvironment determines phenotypic switch of macrophages during the course of AKI and CKD Qi Cao et al. Physiology 2015;30:

30 Microenvironmental Factors controlling Macrophage Phenotype Proinflammatory F4/80+ Wound Healing inos Arg-1 S. Lee J Am Soc Nephrol 22: , 2011 M1 M2 M1 M2 S. Huen and L. Cantley Annu. Rev. Physiol :449 69

31 Mitochondria and Fibrosis M. Zhan Z. Dong, Kidney International (2013) 83, ;

32 Proximal Tubule Deficient of Drp1 is protected from Fibrosis idrp1 WT idrp1 PTKO idrp1 WT idrp1 PTKO idrp1 WT idrp1 PTKO islc34a1creer T2 mouse gift of B. Humphreys HM Perry and MD Okusa unpublished observations 2017

Cardiolipin-protective compound SS31 restores mitochondrial bioenergetics CL phospholipid expressed on the inner mitochondrial membrane; important structural role in cristae formation and the

33 Cardiolipin-protective compound SS31 restores mitochondrial bioenergetics CL phospholipid expressed on the inner mitochondrial membrane; important structural role in cristae formation and the organization of the respiratory complexes into supercomplexes for optimal OX PHOS. The interaction between CL and cytochrome c determines whether cytochrome c acts as an electron carrier or peroxidase. SS-31 is a member of the Szeto-Schiller (SS) peptides targets the inner mitochondrial membrane. SS-31 carries 3+ charge and binds to anionic phospholipid CL. SS-31 prevents CL from converting cytochrome c into a peroxidase - protecting its electron carrying function. SS-31 protects the structure of mitochondrial cristae and promotes oxidative phosphorylation. SS-31 HH Szeto Br J Pharmacol Apr;171(8):

34 HH Szeto et al. JASN November 23, 2016 SS-31 Preserves Mitochondria and arrests CKD Progression IRI SS-31 Euthanize mo Vehicle SS31 Vehicle SS31 Nml n 1 m 2.5 m 9 m

Molecular Mechanisms of Fibrosis Cell Cycle and Epigenetic Modification Rasal 1 RAS inactivation Cell Proliferation Hypermethylation Rasal 1 RAS

35 Molecular Mechanisms of Fibrosis Cell Cycle and Epigenetic Modification Rasal 1 RAS inactivation Cell Proliferation Hypermethylation Rasal 1 RAS activation Cell Proliferation T.A.Wynn Nature Medicine 16, (2010); L. Yang Nature Med 16: , 2010 W. Bechtel Nature Med 16: , 2010

Tgf-b induces proximal tubule partial EMT and cell cycle arrest After injury, TGF-β promotes Snail1 and Twist expression, which activates EMT program incomplete EMT.

36 Tgf-b induces proximal tubule partial EMT and cell cycle arrest After injury, TGF-β promotes Snail1 and Twist expression, which activates EMT program incomplete EMT. Partial EMT cell-cycle arrest to tissue dysfunction. Partial EMT drives proliferation of myofibroblasts by the secretion of growth factors, including TGF-β. Partial EMT fuels chronic inflammation. Yossi Ovadya & Valery Krizhanovsky Nat Med 21: 975, 2015

37 Metabolic alterations in AKI-CKD Metabolic switch in energy metabolism AKI and failed regeneration, PT undergoing atrophy-mitochondrial alterations- persistent glycolytic activity glycolysis, glycolytic enzyme expression Humans and mouse models with tubulointerstitial fibrosis: lower expression of key enzymes and regulators of fatty acid oxidation higher intracellular lipid deposition compared to controls. Inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, seen in fibrosis. Restoration of fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. R. Lan, J.M Weinberg, M.A. Venkatachalam, et al. J Am Soc Nephrol 27: , 2016 H.M. Kang, K. Susztak et al. Nature Medicine 21:37, 2015

38 Acute Kidney Injury and Fibrosis Epithelium Endothelium Hypoxia Cytokines FAO Chemokines Ox Phos Growth Glycolysis Factors Inflammation Microenvironment Mitochondria Structure Mitochondria Function Fibroblast/ Pericyte Capillary Rarefaction Myofibroblast Fibrosis

39 Mark D. Okusa, MD

The Link Between Acute and Chronic Kidney Disease. John Arthur, MD, PhD

The Link Between Acute and Chronic Kidney Disease John Arthur, MD, PhD Conventional Dogma Conventional dogma was that if a patient survived and recovered from AKI, he was unlikely to have long-term sequela.